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Regular monitoring of antiepileptic drug levels in pregnant women with epilepsy does not improve seizure control compared with clinical features-based monitoring. This NIHR-funded study was conducted across 50 UK hospitals and is the largest randomised trial in pregnant women with epilepsy.

Just over 260 pregnant women with unstable antiepileptic drug levels were assigned to ongoing monthly blood checks or clinical features monitoring. There were no differences in seizures or other pregnancy outcomes between the two strategies. But umbilical cord blood showed that babies whose mothers received blood checks were exposed to higher levels of antiepileptic drugs.

The study provides important information about the utility of monitoring blood levels of antiepileptic drugs, which previously was standard clinical practice. NICE guidelines advised against routine monitoring in 2012 and this trial gives support to this recommendation.

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Why was this study needed?

Epilepsy is thought to affect 0.6% of pregnant women in the UK. Uncontrolled epilepsy during pregnancy is associated with increased risk of maternal death in addition to risks to the fetus such as lack of oxygen and miscarriage. By contrast, certain antiepileptic drugs are harmful to the unborn baby, causing congenital abnormalities. However, there is general consensus that controlling seizures in the mother outweighs risk to the fetus, provided the most suitable drugs are used.

During pregnancy, the level of antiepileptic medication in the blood may decrease, and consequently, seizures may occur. American guidelines recommend monitoring blood levels of antiepileptic drugs, and this practice has been used in the UK. But UK guidelines now recommend being guided by clinical features and adjusting medication accordingly.

To date, no randomised controlled trials had compared which method was better at preventing seizures and minimising side effects, and this study meets that need.

What did this study do?

The EMPiRE trial recruited 560 pregnant women (under 24 weeks) with epilepsy from 50 hospitals across the UK. Women who had a 25% or greater decrease in their blood antiepileptic levels compared with pre-pregnancy (263 women) were then randomised to either therapeutic drug monitoring (blood levels measured monthly) or to monitoring of clinical features only.

Researchers had calculated that they needed to recruit at least 660 and the under-recruitment has caused the confidence intervals to be wider than ideal. Therefore a possible small benefit from monitoring can’t be excluded. The study couldn’t analyse seizure risks by individual antiepileptic drug, because the numbers for each were too small. Women taking sodium valproate (no longer recommended during pregnancy) were excluded, as were women taking a combination of drugs unless it involved lamotrigine.

What did it find?

Thirty-eight percent of women in both the therapeutic drug monitoring (48/127) and clinical features monitoring (50/130) groups experienced at least one seizure during pregnancy or up to six weeks after birth.

There was no difference in the main outcome of time to first seizure which was 28 days after randomisation in the therapeutic monitoring group versus 27 days in the clinical features group (hazard ratio [HR] 0.82, 95% confidence interval [CI] 0.55 to 1.20). Neither was there difference when restricting the analysis to time until more serious tonic-clonic seizures (HR 0.80, 95% CI 0.43 to 1.50).

There were no differences between groups in pregnancy outcomes of average gestational age at delivery, preterm birth rate, type of delivery, infant birth weight, Apgar scores, rate of maternal haemorrhage, or admission to a neonatal unit. There was also no difference in breastfeeding rates.

Lamotrigine, levetiracetam and carbamazepine were the drugs taken by all but one recruited individual (taking phenytoin). Infants whose mothers received therapeutic monitoring had higher cord blood levels of lamotrigine (mean difference [MD] 0.55 mg/l, 95% CI 0.11 to 1.0) and levetiracetam (MD 7.8mg/l, 95% CI 0.86 to 14.8) compared with clinical features monitoring. There was no difference between groups in levels of carbamazepine.

What does current guidance say on this issue?

In the UK, NICE and SIGN guidelines advise not to routinely monitor antiepileptic drug levels during pregnancy. Instead, they suggest that monitoring may be useful to guide dose adjustments if seizures increase or are expected to increase, particularly if lamotrigine and phenytoin are being used.

The Royal College of Obstetrics and Gynaecology 2016 guidance on Epilepsy in pregnancy states: “Based on current evidence, routine monitoring of serum antiepileptic levels in pregnancy is not recommended although individual circumstances may be taken into account”.

A review of the NICE guideline Epilepsies in adults: diagnosis and management is currently underway, with an expected publication date of 20 January 2021.

What are the implications?

This study supports the change in national guideline recommendations against routine monitoring of antiepileptic levels during pregnancy. It suggests therapeutic monitoring gives little or no benefit while increasing fetal exposure to potentially harmful antiepileptic drugs.

The insufficient recruitment is a limitation, which does mean the researchers have not ruled out a small benefit. One reason for this is that a number of UK centres declined participation as treating doctors considered one strategy to be preferable to the other. This trial may provide evidence to standardise practice and help women to be fully informed around appropriate treatment of epilepsy during pregnancy.

Why was this study needed?

Epilepsy is thought to affect 0.6% of pregnant women in the UK. Uncontrolled epilepsy during pregnancy is associated with increased risk of maternal death in addition to risks to the fetus such as lack of oxygen and miscarriage. By contrast, certain antiepileptic drugs are harmful to the unborn baby, causing congenital abnormalities. However, there is general consensus that controlling seizures in the mother outweighs risk to the fetus, provided the most suitable drugs are used.

During pregnancy, the level of antiepileptic medication in the blood may decrease, and consequently, seizures may occur. American guidelines recommend monitoring blood levels of antiepileptic drugs, and this practice has been used in the UK. But UK guidelines now recommend being guided by clinical features and adjusting medication accordingly.

To date, no randomised controlled trials had compared which method was better at preventing seizures and minimising side effects, and this study meets that need.

What did this study do?

The EMPiRE trial recruited 560 pregnant women (under 24 weeks) with epilepsy from 50 hospitals across the UK. Women who had a 25% or greater decrease in their blood antiepileptic levels compared with pre-pregnancy (263 women) were then randomised to either therapeutic drug monitoring (blood levels measured monthly) or to monitoring of clinical features only.

Researchers had calculated that they needed to recruit at least 660 and the under-recruitment has caused the confidence intervals to be wider than ideal. Therefore a possible small benefit from monitoring can’t be excluded. The study couldn’t analyse seizure risks by individual antiepileptic drug, because the numbers for each were too small. Women taking sodium valproate (no longer recommended during pregnancy) were excluded, as were women taking a combination of drugs unless it involved lamotrigine.

What did it find?

Thirty-eight percent of women in both the therapeutic drug monitoring (48/127) and clinical features monitoring (50/130) groups experienced at least one seizure during pregnancy or up to six weeks after birth.

There was no difference in the main outcome of time to first seizure which was 28 days after randomisation in the therapeutic monitoring group versus 27 days in the clinical features group (hazard ratio [HR] 0.82, 95% confidence interval [CI] 0.55 to 1.20). Neither was there difference when restricting the analysis to time until more serious tonic-clonic seizures (HR 0.80, 95% CI 0.43 to 1.50).

There were no differences between groups in pregnancy outcomes of average gestational age at delivery, preterm birth rate, type of delivery, infant birth weight, Apgar scores, rate of maternal haemorrhage, or admission to a neonatal unit. There was also no difference in breastfeeding rates.

Lamotrigine, levetiracetam and carbamazepine were the drugs taken by all but one recruited individual (taking phenytoin). Infants whose mothers received therapeutic monitoring had higher cord blood levels of lamotrigine (mean difference [MD] 0.55 mg/l, 95% CI 0.11 to 1.0) and levetiracetam (MD 7.8mg/l, 95% CI 0.86 to 14.8) compared with clinical features monitoring. There was no difference between groups in levels of carbamazepine.

What does current guidance say on this issue?

In the UK, NICE and SIGN guidelines advise not to routinely monitor antiepileptic drug levels during pregnancy. Instead, they suggest that monitoring may be useful to guide dose adjustments if seizures increase or are expected to increase, particularly if lamotrigine and phenytoin are being used.

The Royal College of Obstetrics and Gynaecology 2016 guidance on Epilepsy in pregnancy states: “Based on current evidence, routine monitoring of serum antiepileptic levels in pregnancy is not recommended although individual circumstances may be taken into account”.

A review of the NICE guideline Epilepsies in adults: diagnosis and management is currently underway, with an expected publication date of 20 January 2021.

What are the implications?

This study supports the change in national guideline recommendations against routine monitoring of antiepileptic levels during pregnancy. It suggests therapeutic monitoring gives little or no benefit while increasing fetal exposure to potentially harmful antiepileptic drugs.

The insufficient recruitment is a limitation, which does mean the researchers have not ruled out a small benefit. One reason for this is that a number of UK centres declined participation as treating doctors considered one strategy to be preferable to the other. This trial may provide evidence to standardise practice and help women to be fully informed around appropriate treatment of epilepsy during pregnancy.

Background
Pregnant women with epilepsy on antiepileptic drugs (AEDs) may experience a reduction in serum AED levels. This has the potential to worsen seizure control.
Objective
To determine if, in pregnant women with epilepsy on AEDs, additional therapeutic drug monitoring reduces seizure deterioration compared with clinical features monitoring after a reduction in serum AED levels.
Design
A double-blind, randomised trial nested within a cohort study was conducted and a qualitative study of acceptability of the two strategies was undertaken. Stratified block randomisation with a 1 : 1 allocation method was carried out.
Setting
Fifty obstetric and epilepsy clinics in secondary and tertiary care units in the UK.
Participants
Pregnant women with epilepsy on one or more of the following AEDs: lamotrigine, carbamazepine, phenytoin or levetiracetam. Women with a ≥ 25% decrease in serum AED level from baseline were randomised to therapeutic drug monitoring or clinical features monitoring strategies.
Interventions
In the therapeutic drug monitoring group, clinicians had access to clinical findings and monthly serum AED levels to guide AED dosage adjustment for seizure control. In the clinical features monitoring group, AED dosage adjustment was based only on clinical features.
Main outcome measures
Primary outcome – seizure deterioration, defined as time to first seizure and to all seizures after randomisation per woman until 6 weeks post partum. Secondary outcomes – pregnancy complications in mother and offspring, maternal quality of life, seizure rates in cohorts with stable serum AED level, AED dose exposure and adverse events related to AEDs.
Analysis
Analysis of time to first and to all seizures after randomisation was performed using a Cox proportional hazards model, and multivariate failure time analysis by the Andersen–Gill model. The effects were reported as hazard ratios (HRs) with 95% confidence intervals (CIs). Secondary outcomes were reported as mean differences (MDs) or odds ratios.
Results
A total of 130 women were randomised to the therapeutic drug monitoring group and 133 to the clinical features monitoring group; 294 women did not have a reduction in serum AED level.
A total of 127 women in the therapeutic drug monitoring group and 130 women in the clinical features monitoring group (98% of complete data) were included in the primary analysis. There were no significant differences in the time to first seizure (HR 0.82, 95% CI 0.55 to 1.2) or timing of all seizures after randomisation (HR 1.3, 95% CI 0.7 to 2.5) between both trial groups. In comparison with the group with stable serum AED levels, there were no significant increases in seizures in the clinical features monitoring (odds ratio 0.93, 95% CI 0.56 to 1.5) or therapeutic drug monitoring group (odds ratio 0.93, 95% CI 0.56 to 1.5) associated with a reduction in serum AED levels. Maternal and neonatal outcomes were similar in both groups, except for higher cord blood levels of lamotrigine (MD 0.55 mg/l, 95% CI 0.11 to 1 mg/l) or levetiracetam (MD 7.8 mg/l, 95% CI 0.86 to 14.8 mg/l) in the therapeutic drug monitoring group than in the clinical features monitoring group. There were no differences between the groups on daily AED exposure or quality of life. An increase in exposure to lamotrigine, levetiracetam and carbamazepine significantly increased the cord blood levels of the AEDs, but not maternal or fetal complications. Women with epilepsy perceived the need for weighing up their increased vulnerability to seizures during pregnancy against the side effects of AEDs.
Limitations
Fewer women than the original target were recruited.
Conclusion
There is no evidence to suggest that regular monitoring of serum AED levels in pregnancy improves seizure control or affects maternal or fetal outcomes.
Future work recommendations
Further evaluation of the risks of seizure deterioration for various threshold levels of reduction in AEDs and the long-term neurodevelopment of infants born to mothers in both randomised groups is needed. An individualised prediction model will help to identify those women who need close monitoring in pregnancy.
Funding
This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 22, No. 23. See the NIHR Journals Library website for further project information.

Expert commentary

This trial showed no difference in maternal or fetal outcomes when women with epilepsy whose antiepileptic drug levels decreased during pregnancy were monitored either clinically or with therapeutic drug monitoring.

Although the trial was underpowered, reassuringly more than half of women, irrespective of the monitoring strategy used, did not have any seizures after entry into the trial. All were seen regularly in secondary or tertiary obstetric and/or epilepsy clinics which may partly explain their good outcomes, and could be considered the main take-home message for clinical care.

Importantly, however, cord blood levels of antiepileptic drugs were higher in the women who had blood monitoring, suggesting greater fetal exposure with no apparent clinical benefit. Long-term follow-up of these children is essential.

Marian Knight, Professor of Maternal and Child Population Health, University of Oxford